The present invention relates to novel therapeutic uses of a known compound, gabapentin, its derivatives, and pharmaceutically acceptable salts. The present invention concerns a method for treating neurodegenerative disorders in a mammal in need of such treatment.
Such neurodegenerative disorders are, for example, Alzheimer's disease, Huntington's disease, Parkinson's disease, and Amyotrophic Lateral Sclerosis.
The present invention also covers treating neurodegenerative disorders termed acute brain injury. These include but are not limited to: stroke, head trauma, and asphyxia.
Stroke refers to a cerebral vascular disease and may also be referred to as a cerebral vascular incident (CVA) and includes acute thromboembolic stroke. Stroke includes both focal and global ischemia. Also included are transient cerebral ischemic attacks and other cerebral vascular problems accompanied by cerebral ischemia. A patient undergoing carotid endarterectomy specifically or other cerebrovascular or vascular surgical procedures in general, or diagnostic vascular procedures including cerebral angiography and the like.
Other incidents are head trauma, spinal cord trauma, or injury from general anoxia, hypoxia, hypoglycemia, hypotension as well as similar injuries seen during procedures from embole, hyperfusion, and hypoxia.
The instant invention would be useful in a range of incidents, for example, during cardiac bypass surgery, in incidents of intracranial hemorrhage, in perinatal asphyxia, in cardiac arrest, and status epilepticus.
A skilled physician will be able to determine the appropriate situation in which subjects are susceptible to or at risk of, for example, stroke as well as suffering from stroke for administration by methods of the present invention.
U.S. Pat. No. 4,024,175 and its divisional U.S. Pat. No. 4,087,544 cover the compounds of the instant invention, methods for preparing them, and several uses thereof. The uses disclosed are: protective effect against cramp induced by thiosemicarbazide; protective action against cardiazole cramp; the cerebral diseases epilepsy, faintness attacks, hypokinesia, and cranial traumas; and improvement in cerebral functions. The compounds are useful in geriatric patients. The patents are hereby incorporated by reference.
The N-methyl-D-aspartic acid (NMDA) receptor is the best characterized of the receptor subtypes mediating the effects of the excitatory amino acid neurotransmitters. To date, the majority of compounds modulating activity at the NMDA receptor channel complex have been competitive or noncompetitive antagonists, i.e., D-APV (which is D-2-amino-5-phosphonovaleric acid) and MK-801 (which is dizocilpine or (+)-5-methy-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine), respectively.
Recently it has been shown that NMDA responses in cultured cerebral neurons were greatly potentiated in the presence of submicromolar concentrations of glycine (Johnson and Ascher (1987), Nature 325, 529-531). Glycine potentiates the NMDA response in cultured mouse brain neurons. This site is strychnine insensitive, and therefore appears unrelated to the classical inhibitory glycine receptor. Since this glycine potentiation occurs at concentrations similar to those found in the extracellular solution surrounding neurons in vivo, the possibility exists that drugs may antagonize the actions of excitatory amino acids acting at the NMDA receptor by a selective action at the glycine modulatory site.
The overstimulation of NMDA receptors is thought to be involved in the etiology of several neurological disorders, i.e., epilepsy and cerebral ischemia. Evidence is also accumulating that the brain damage associated with anoxia, stroke, hypoglycemia, epilepsy and perhaps neurodegenerative illnesses such as Huntingdon's disease may be at least partially produced by excessive activation of NMDA receptors (Kemp, J.A., Foster, A.C., Wong, E.H.F. (1987). Non-competitive antagonists of excitatory amino acid receptors. Trends in Neurosciences 10(7), 294-298).
Since NMDA receptor activation is implicated in the generation of neurodegenerative diseases, and since glycine potentiates responses to NMDA, there is an enormous therapeutic potential for drugs which antagonize the actions of glycine at the modulatory site of the NMDA receptor.
The striatum receives a major neuronal input from the cortex, and this corticostriatal pathway is believed to use L-glutamate as its excitatory neurotransmitter. There is biochemical evidence for glutamate as a neurotransmitter in corticostriatal and corticothalamic fibers in the rat brain. (Fonnum, F., Storm-Mathisen, J., Divac, I. (1981), Neuroscience 6, 863-873.)
Previous in vitro studies have shown that excitatory amino acids are able to elicit responses from striatal neurons in brain slices and in dissociated culture. (Cherubini, E., Gerrling, P.L., Lanfumey, L., Stanzione, P. (1988). Excitatory amino acids in synaptic excitation of rat striatal neurons in vitro. J. Physiol. 400, 677-690; Ascher, P., Gregestovski, P., Nowal, L. (1988). NMDA activated channels of mouse central neurons in magnesium-free solutions. J. Physiol. 399, 207-226; Sprosen, T. S., Boden, P. R., Hughes, J. (1989). The development of excitatory amino acid responses in dissociated cultures of fetal rat striatum. European Neuroscience Association Abstract, Turin, Italy. 15.12 p43.)
Gabapentin has been shown to protect mice from seizures elicited by 4-aminobutanoic acid (GABA) synthesis or GABA receptor antagonists. Furthermore, it was found to prolong the latency of onset of seizures elicited by NMDA (Bartoszyk, G.D., Fritschi, E., Herrman, M., Satzinger, G. (1983). Indications for an involvement of the GABA-system in the mechanism of action of gabapentin. Naunyn-Schmiedeberg's Arc. Pharmacol. 322 R94). In mechanistic terms, the anticonvulsant action of gabapentin appears to be unrelated to an action on GABA systems, since it does not displace GAB.sub.A or GABA.sub.B binding and does not interfere with neuronal GABA uptake.
This study provides a possible mechanism for the anticonvulsant action of gabapentin, i.e., that it acts as a partial agonist at the glycine modulatory site of the NMDA receptor-channel complex. The partial agonist nature of gabapentin is reflected in its ability to antagonize the actions of glycine at the modulatory site, and its ability to potentiate response to NMDA (due to its agonist action at the glycine modulatory site, in the absence of exogenous glycine).
Since glycine potentiates responses to NMDA at physiological concentrations, gabapentin will act to antagonize the actions of endogenous glycine at the modulatory site and hence `damp-down` the effects of NMDA receptor activation.
In addition to its anticonvulsant actions, these results indicate that gabapentin has additional therapeutic indications. Overstimulation of NMDA receptors has been implicated in the etiology of neuronal damage induced by anoxia, stroke, hypoglycemia, Huntington's disease, as well as epilepsy.
There is no disclosure in the above references to make obvious the present invention of novel uses of compounds of U.S. Pat. No. 4,024,175 to treat neurodegenerative disorders.